Concussion symptom presentation and clinical recovery among pediatric athletes: comparing concussions sustained during school and summer months.

OBJECTIVE: We examined post-concussion symptom presentation, exercise, and sleep among pediatric athletes who sustained concussion during the school year vs. summer months. METHODS: We evaluated athletes 6-18 years old within 21-days of concussion. They reported symptoms (Health and Behavior Inventory), with cognitive/somatic domain sub-scores calculated, and indicated if they had exercised or experienced sleep problems since injury. We grouped patients by injury season: summer months (June-August) vs. school year (September-May). RESULTS: 350 patients (14.4 ± 2.4 years old; 37% female; initial visit 8.8 ± 5.3 days post-concussion) were seen for care: 24% sustained a concussion during summer months, 76% during the school year. Lower cognitive (median = 7 [IQR = 1, 15] vs. 9.5 [4, 17]; p = 0.01), but not somatic (7 [2.5, 11] vs. 8 [4, 13]; p = 0.06), HBI scores were observed for patients injured during the summer. Groups were similar in proportion exercising (16% vs 17%) and endorsing sleep problems (29% vs 31%). After adjustments, sustaining a concussion during the summer predicted total (ß=-3.43; 95%CI = -6.50, -0.36; p = 0.029) and cognitive (ß = -2.29; 95%CI = -4.22, -0.36; p = 0.02), but not somatic (ß=-1.46; 95%CI = -2.84, -0.08; p = 0.04), symptom severity. CONCLUSION: Pediatric patients with concussion may present with greater cognitive symptoms during the school year, compared to summer months.

The Diagnostic Utility of Cervical Spine Proprioception for Adolescent Concussion.

OBJECTIVE: Cervical spine proprioception may be impaired after concussion. Our objective was to determine the diagnostic utility of cervical spine proprioception for adolescent concussion. DESIGN: Cross-sectional. SETTING: Research laboratory. PARTICIPANTS: Adolescents ≤18 days of concussion and uninjured controls. INTERVENTIONS: N/A. MAIN OUTCOMES: Head repositioning accuracy (HRA) testing, a measure of cervical spine proprioception. The HRA test involved patients relocating their head back to a neutral starting position with eyes closed after maximal cervical spine flexion, extension, and right and left rotations. The overall HRA error score was the mean error (distance from the starting point to self-reported return to neutral) across 12 trials: 3 trials in each direction. We used t-tests to compare group means and logistic regression (outcome = group, predictor = HRA, covariates) to calculate odds ratios. We used a receiver operator characteristic curve to evaluate area under the curve (AUC) and calculate the optimal HRA cutpoint to distinguish concussion from controls. RESULTS: We enrolled and tested 46 participants with concussion (age = 15.8 ± 1.3 years, 59% female, mean = 11.3 ± 3.3 days postconcussion) and 83 uninjured controls (age = 16.1 ± 1.4 years, 88% female). The concussion group had significantly worse HRA than controls (4.3 ± 1.6 vs 2.9 ± 0.7 degrees, P < 0.001, Cohen d = 1.19). The univariable HRA model AUC was 0.81 (95% CI = 0.73, 0.90). After adjusting for age, sex, and concussion history, the multivariable model AUC improved to 0.85 (95% CI = 0.77, 0.92). The model correctly classified 80% of participants as concussion/control at a 3.5-degree cutpoint. CONCLUSIONS: Adolescents with concussion demonstrated worse cervical spine proprioception than uninjured controls. Head repositioning accuracy may offer diagnostic utility for subacute concussion.

Factors Associated with Symptom Resolution after Aerobic Exercise Intervention in Adolescent and Young Adults with Concussion.

BACKGROUND: Aerobic exercise facilitates postconcussion symptom resolution at the group level, but patient-level characteristics may affect the likelihood of treatment efficacy. PURPOSE: This study aimed to investigate demographic and clinical characteristics, which differentiate postconcussion aerobic exercise treatment efficacy from nonefficacy in the intervention arm of a randomized clinical trial. METHODS: Adolescent and young adult participants initiated a standardized aerobic exercise intervention within 14 d of concussion, consisting of self-selected exercise for 100 min·wk -1 at an individualized heart rate (80% of heart rate induced symptom exacerbation during graded exercise testing). Treatment efficacy was defined as symptom resolution within 28-d postconcussion. Treatment efficacy and nonefficacy groups were compared on demographics, clinical characteristics, intervention adherence, and persistent symptom risk using the Predicting Persistent Postconcussive Problems in Pediatrics (5P) clinical risk score. RESULTS: A total of 27 participants (16.1 ± 2.3 yr old; range, 11-21 yr; 52% female) began the intervention, with a mean of 9.5 ± 3.7 d after concussion; half ( n = 13; 48%) demonstrated treatment efficacy (symptom resolution within 28 d postconcussion). Those whose symptoms resolved within 28 d had significantly lower preintervention postconcussion symptom inventory scores (21.2 ± 13.2 vs 41.4 ± 22.2; P < 0.01), greater adherence to the intervention (77% vs 36%; P = 0.05), and longer average exercise duration (median [interquartile range], 49.7 [36.8-68.6] vs 30.4 [20.7-34.7] min; P < 0.01) than those whose symptoms lasted more than 28 d. Groups were similar in age, sex, timing of intervention, and preintervention 5P risk score. CONCLUSIONS: A standardized aerobic exercise intervention initiated within 14 d of concussion demonstrated efficacy for approximately half of participants, according to our definition of treatment efficacy. This multisite aerobic exercise intervention suggests that lower symptom severity, higher intervention adherence, and greater exercise duration are factors that increase the likelihood of symptoms resolving within 28 d of concussion.

Postconcussion Moderate to Vigorous Physical Activity Predicts Anxiety Severity among Adolescent Athletes.

PURPOSE: This study aimed to examine how moderate-to-vigorous physical activity (MVPA) during concussion recovery influences self-reported anxiety symptoms at follow-up assessment. We hypothesized that more MVPA after concussion would be associated with lower anxiety rating at follow-up. METHODS: We performed a prospective study of participants aged 13-18 yr initially assessed within 14 d of diagnosed concussion. Participants rated concussion symptoms using the Post-Concussion Symptom Inventory and were provided a wrist-worn actigraphy device to track activity for 1 wk after assessment. At follow-up assessment, participants rated anxiety symptoms using the four-question Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety subscale. Each question ranged from 1 (never) to 5 (almost always), with an overall score range of 4-20. For univariable analysis, we calculated correlation coefficients between MVPA and PROMIS anxiety subscale scores. We then created a multiple linear regression model with follow-up PROMIS anxiety subscale score as the outcome and MVPA, sex, initial symptom severity, and preconcussion anxiety as predictors. RESULTS: We enrolled and initially tested 55 participants, and 48 were included in the final analysis (age, 14.6±2.7 yr; 56% female; initial assessment, 7.3± 3.1 d; follow-up assessment, 42.0±29.7 d). We observed an inverse and low correlation between MVPA and follow-up PROMIS anxiety subscale T-scores ( r = -0.30, P = 0.04). Multivariable regression results indicated that MVPA ( ß = -5.30; 95% confidence interval (CI), -10.58 to -0.01), initial Post-Concussion Symptom Inventory score ( ß = 0.11; 95% CI, 0.03 to 0.19), and preconcussion anxiety ( ß = 5.56; 95% CI, 0.12 to 11.0), but not sex ( ß = -2.60; 95% CI, -7.14, to 1.94), were associated with follow-up PROMIS anxiety subscale T-scores. CONCLUSIONS: After adjusting for covariates, more MVPA early after concussion predicted lower PROMIS anxiety subscale scores at follow-up. Although initial concussion symptom severity and preconcussion anxiety were also associated with follow-up PROMIS anxiety subscale score, MVPA represents a modifiable factor that may contribute to lower anxiety symptoms.

Cervical spine proprioception and vestibular/oculomotor function: An observational study comparing young adults with and without a concussion history.

OBJECTIVE: To investigate dizziness, vestibular/oculomotor symptoms, and cervical spine proprioception among adults with/without a concussion history. METHODS: Adults ages 18-40 years with/without a concussion history completed: dizziness handicap inventory (DHI), visio-vestibular exam (VVE), and head repositioning accuracy (HRA, assesses cervical spine proprioception). Linear regression models were used to assess relationships between (1) concussion/no concussion history group and VVE, HRA, and DHI, and (2) DHI with HRA and VVE for the concussion history group. RESULTS: We enrolled 42 participants with concussion history (age = 26.5 ± 4.5 years, 79% female, mean = 1.4± 0.8 years post-concussion) and 46 without (age = 27.0± 3.8 years, 74% female). Concussion history was associated with worse HRA (ß = 1.23, 95% confidence interval [CI]: 0.77, 1.68; p < 0.001), more positive VVE subtests (ß = 3.01, 95%CI: 2.32, 3.70; p < 0.001), and higher DHI scores (ß = 9.79, 95%CI: 6.27, 13.32; p < 0.001) after covariate adjustment. For the concussion history group, number of positive VVE subtests was significantly associated with DHI score (ß = 3.78, 95%CI: 2.30, 5.26; p < 0.001) after covariate adjustment, while HRA error was not (ß = 1.10, 95%CI: -2.32, 4.51; p = 0.52). CONCLUSIONS: Vestibular/oculomotor symptom provocation and cervical spine proprioception impairments may persist chronically (i.e., 3 years) after concussion. Assessing dizziness, vestibular/oculomotor and cervical spine function after concussion may inform patient-specific treatments to address ongoing dysfunction.

Variables associated with days of school missed following concussion: results from the Sport Concussion Outcomes in PEdiatrics (SCOPE) study.

OBJECTIVE: To understand factors associated with missed academic time after concussion to improve support for patients. Our goal was to assess patient-specific predictors of total school time lost after pediatric/adolescent concussion. STUDY DESIGN: We performed a prospective cohort study of children and adolescents (8-18 years of age) seen within 14 days of concussion from seven pediatric medical centers across the United States. We collected outcomes via the Concussion Learning Assessment & School Survey (CLASS) and constructed a multivariable predictive model evaluating patient factors associated with school time loss. RESULTS: 167 patients participated (mean age = 14.5 ± 2.2 years; 46% female). Patients were assessed initially at 5.0 ± 3.0 days post-injury and had a final follow-up assessment 24.5 ± 20.0 days post-concussion. Participants missed a median of 2 days of school (IQR = 0.5-4), and 21% reported their grades dropped after concussion. Higher initial symptom severity rating (ß = 0.06, 95% CI = 0.03-0.08, p < 0.001) and perception of grades dropping after concussion (ß = 1.37, 95% CI = 0.28-2.45, p = 0.01) were significantly associated with more days of school time missed after concussion. Those who reported their grades dropping reported missing significantly more school (mean = 5.0, SD = 4.7 days missed of school) than those who reported their grades did not drop (mean = 2.2, SD = 2.6 days missed of school; p < 0.001; Cohen's d = 0.87). CONCLUSIONS: Children and adolescents reported missing a median of 2 days of school following concussion, and more missed school time after a concussion was associated with more severe concussion symptoms and perception of grades dropping. These findings may support recommendations for minimal delays in return-to-learn after concussion.

Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells.

Gemcitabine is a potent inhibitor of DNA replication and is a mainstay therapeutic for diverse cancers, particularly pancreatic ductal adenocarcinoma (PDAC). However, most tumors remain refractory to gemcitabine therapies. Here, to define the cancer cell response to gemcitabine, we performed genome-scale CRISPR-Cas9 chemical-genetic screens in PDAC cells and found selective loss of cell fitness upon disruption of the cytidine deaminases APOBEC3C and APOBEC3D. Following gemcitabine treatment, APOBEC3C and APOBEC3D promote DNA replication stress resistance and cell survival by deaminating cytidines in the nuclear genome to ensure DNA replication fork restart and repair in PDAC cells. We provide evidence that the chemical-genetic interaction between APOBEC3C or APOBEC3D and gemcitabine is absent in nontransformed cells but is recapitulated across different PDAC cell lines, in PDAC organoids and in PDAC xenografts. Thus, we uncover roles for APOBEC3C and APOBEC3D in DNA replication stress resistance and offer plausible targets for improving gemcitabine-based therapies for PDAC.

Deciphering complexity in Pd-catalyzed cross-couplings.

Understanding complex reaction systems is critical in chemistry. While synthetic methods for selective formation of products are sought after, oftentimes it is the full reaction signature, i.e., complete profile of products/side-products, that informs mechanistic rationale and accelerates discovery chemistry. Here, we report a methodology using high-throughput experimentation and multivariate data analysis to examine the full signature of one of the most complicated chemical reactions catalyzed by palladium known in the chemical literature. A model Pd-catalyzed reaction was selected involving functionalization of 2-bromo-N-phenylbenzamide and multiple bond activation pathways. Principal component analysis, correspondence analysis and heatmaps with hierarchical clustering reveal the factors contributing to the variance in product distributions and show associations between solvents and reaction products. Using robust data from experiments performed with eight solvents, for four different reaction times at five different temperatures, we correlate side-products to a major dominant N-phenyl phenanthridinone product, and many other side products.